ASH 2024 preview – Arcellx disappoints

First the good news for Arcellx: its BCMA-targeting Car-T contender anitocabtagene autoleucel was, as hoped, not linked to delayed neurotoxicity, ASH abstracts revealed on Tuesday. However, the bad news was that three deaths were seen among 58 patients in the phase 2 Immagine-1 trial, including one from cytokine release syndrome.

It is unclear how many of the fatalities are attributable to anito-cel, which is partnered with Gilead: the ASH abstract notes that the deaths were related and unrelated to therapy, but didn’t give more details. However, efficacy is looking no better than Johnson & Johnson/Legend’s marketed Car-T therapy, Carvykti.

Investors sent Arcellx down 7% on Tuesday morning, perhaps on fears that the group, already behind, will struggle to compete; however, by the end of the day the stock had recovered, closing up 1%. 

On ORR anito-cel looks in line with Carvykti, according to a cross-trial comparison of Immagine-1, in fourth-line multiple myeloma, and the analogous Cartitude-1 study. However, Carvykti looks better on complete response rates.

Cross-trial comparison of anito-cel vs Carvykti

Note: *Cutoff date 1 Jun 2024; Source: ASH 2024 abstract & Carvykti label.

Still, similar or slightly worse efficacy was always the realistic hope. Ahead of the abstract drop, Evercore ISI’s Cory Kasimov had noted that anito-cel would struggle to surpass Carvykti’s impressive data, concluding: “Comparable is good enough.”

Rather, anito-cel’s unique selling point is its “smaller and simpler” synthetic binding domain, which could lead to better manufacturability and, potentially, safety.

Similar efficacy, better safety?

This was borne out by the ASH data, according to Kasimov, who noted zero cases of delayed neurotoxicity – including no parkinsonism, no cranial nerve palsies, and no Guillain-Barré syndrome – among over 140 patients receiving anito-cel so far, across both Immagine-1 and a phase 1 trial in late-line multiple myeloma.

Meanwhile, around 7% of patients in the Cartitude-1 and Cartitude-4 trials of Carvykti experienced grade 3 or higher neurotoxicity, according to that product’s label; grade 3 or greater parkinsonism was seen in 2% of patients.

Even so, anito-cel doesn’t look completely blemish free, with three deaths in Immagine-1 due to “related and unrelated” adverse events of retroperitoneal haemorrhage, CRS and fungal infection. Presumably the ASH presentation will give more information, but Kasimov noted that the CRS fatality involved a 76-year-old patient "who was not bridged well [and] lacked an underlying physiological capability to fight the onset of symptoms".

Immagine-1 was previously put on clinical hold following a patient death, but this was quickly lifted, and it was revealed that the patient had received the Car-T therapy despite becoming ineligible for it.

Carvykti itself has been linked with a high rate of early death, although some fears have more recently been assuaged.

Overall, Kasimov dubbed the latest anito-cel results “compelling”, suggesting the stock market reaction involved an element of selling the news.

Still, there’s a question of how an approved anito-cel might fit into the BCMA Car-T landscape, given Carvykti’s recent second-line approval and a resulting sales boost. Gilead and Arcellx are also looking to earlier settings and have now dosed the first patient in their second-line phase 3 Immagine-3 study, they said on Tuesday.

ASH will take place on 7-10 December in San Diego.

This story has been updated.